GB2274777A - Synergistic compositions containing NK1 and NK2 receptor antagonists - Google Patents

Abstract

Combinations comprising at least one compound with an antagonist activity towards NK1 receptors and at least one with an antagonist activity towards NK2 receptors, are synergistic and advantageous in the treatment of complaints where Substance P and/or neurokinin A are involved. Typical activity is in treatment of pain, anxiety, Alzheimes and Parkinsons diseases, respiratory and digestive tract ailments, hypotension etc. Exhaustive lists of suitable antagonists are given.

Description

SYNERGISTIC COMBINATION OF COMPOUNDS HAVING AN ANTAGONIST EFFECT ON NK1 AND ON NK2 RECEPTORS The present invention provides synergistic combinations of at least one antagonist of NKl receptors and at least one antagonist of NK2 receptors.

Substance P and neurokinin A are neuropeptides of the tachykinin family. Tachykinins are endogenous ligands known to be able to stimulate 3 types of receptors known as NK1, NK2 and NK3 receptors.

The effects of Substance P are mainly mediated by NK1 receptors. The effects of neurokinin A are mainly mediated by NK2 receptors.

Substance P is an undecapeptide which is implicated in many pathologies such as, for example, transmission of pain, disorders of the central nervous system, inflammatory or respiratory phenomena, and the like.

Neurokinin A is also implicated in numerous pathologies such as transmission of pain, arthritis, asthma, inflammatory phenomena, psychoses, tensional disorders, vesical disorders, cystites, and the like.

Until recently (of M.R. Hanley, TINS, (5) 139 (1982)), no product acting specifically on Substance P or on neurokinin A and having a non-peptide structure had been discovered.

Antagonists of NK1 receptors (antagonists of the effects of Substance P) are now known and have been described especially in Patent Applications EP 429,366, EP 514,273, EP 514,275, WO 90/05525, WO 90/05729, WO 91/18899, WO 91/09844, WO 92/01688, WO 92/06079, WO 92/15585, WO 92/12151, WO 92/20661, WO 92/20676, WO 92/21677, WO 93/00330, WO 93/00331, WO 93/01159, WO 93/01169, WO 93/01165, WO 93/01170, WO 93/06099, WO 93/09116, WO 93/10073, WO 93/18023, WO 93/19064, WO 93/21155, WO 93/21181, WO 93/23380, EP 499,313, EP 394,989, EP 443,132, EP 482,539, EP 512,902, EP 517,589, EP 520,555, EP 522,808, EP 528,495, EP 532,456, EP 533,280, EP 536,817, EP 545,478, and EP 559,538. See also the XIIth Int. Symp. on Med.

Chem., Basle, 13-17 September 1992 or 3rd Meeting of the European Neuropeptide Club (Cambridge, 5-7 April 1993).

Antagonists of NR2 receptors (antagonists of the effects of neurokinin A) are also known and have been described especially in Patent Applications EP 428,434, EP 474,561, EP 512,901, EP 515,240, FR 2,678,267, WO 92/19254 and WO 93/14084.

It has also been disclosed that certain compounds have antagonist activity towards NK1 receptors and antagonist activity towards NK2 receptors: M. Murai et al., J. Pharm. Exp. Ther., 262(1), 403 (1992). However, none of these compounds has shown a very high activity.

Until now, it has been supposed that the effects of antagonists of NK1 and NK2 receptors could act similarly and additively on certain functional groups. It has, however, now been found that the effects of a combination of antagonists of NK1 receptors and antagonists of NK2 receptors are potentiated. This opens a particularly advantageous route into therapeutic fields where Substance P and/or neurokinin A are involved.

The present invention therefore provides a combination, having synergistic properties and are useful in the treatment of complaints involving substance P and/or neurokinin A, comprising at least one compound having an antagonist activity towards NK1 receptors and at least one compound having an antagonist activity towards NK2 receptors.

As non-limiting examples, antagonists of NK1 receptors can be especially derivatives of the perhydroisoindole class, derivatives of the 2-substituted-3-aminoquinuclidine class, derivatives of the aminoazabicycloalkane class, derivatives of the 2-substituted-3-aminopiperidine class, derivatives of the 1-azabicyclo(3 .2 .2)nonan-3-amine class, derivatives of the N-alkylquinuclidinium salt class, derivatives of the pseudopeptide class, derivatives of the N,N-diacylpiperazine class, substituted aromatic derivatives, dialkylenepiperidino derivatives, quaternary salts of substituted piperidines, and the like.

By way of example, products of the class of perhydroisoindole derivatives can have the structure:

and their salts, when they exist, in which: - the Rl symbol represents a phenyl radical optionally substituted by one or a number of halogen atoms or hydroxyl radicals, alkyl radicals which can optionally be substituted (by halogen atoms or amino, alkylamino or dialkylamino radicals), alkyloxy or alkylthio radicals which can optionally be substituted (by optionally substituted (by phenyl, hydroxyl or amino radicals) dialkylamino, alkylamino, amino or hydroxyl radicals, or dialkylamino radicals in which the alkyl parts form, with the nitrogen atom to which they are attached, a 5- to 6-membered heterocycle which can contain another heteroatom chosen from oxygen, sulphur or nitrogen, optionally substituted by an alkyl, hydroxyl or hydroxyalkyl radical, or substituted by amino, alkylamino or dialkylamino radicals in which the alkyl parts can form, with the nitrogen atom to which they are attached, a heterocycle as defined above, or represents a cyclohexadienyl radical, a naphthyl radical or a saturated or unsaturated, mono- or polycyclic heterocyclyl radical (5 to 9 carbon atoms) containing one or a number of heteroatoms chosen from oxygen, nitrogen or sulphur, and optionally substituted by a halogen atom or by an alkyl or alkyloxy radical, - the R2 symbol represents a hydrogen or halogen atom or a hydroxyl, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxyl, alkyloxycarbonyl, dialkylaminoalkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino radical, - the bicyclic structure::

represents a perhydroisoindole or thiapyranopyrrole ring of general formula:

and the symbol X represents an oxygen or sulphur atom or a radical NR6 in which R6 is a hydrogen atom, an alkyl radical containing 1 to 12 carbon atoms and optionally substituted tby one or a number of carboxyl, dialkylamino, acylamino, alkyloxycarbonyl, alkyloxycarbonylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl radicals (it being possible for the alkyl portions of these substituents to themselves be substituted by dialkylamino or phenyl) or substituted by phenyl, substituted phenyl (substituted by halogen, alkyl, alkyloxy or dialkylamino), naphthyl, thienyl, furyl, pyridyl or imidazolyl radicals) or a dialkylamino radical, or else, if the ring is of formula (Ib) or (Ic), the symbol X represents an oxygen atom, or an NH radical, or else - the bicyclic structure:

represents a perhydroisoindole or thiapyranopyrrole ring of general formula:

and the symbol X represents an oxygen atom.

In the general formulae (Ia) to (Ie): - the R symbols are identical and represent phenyl radicals optionally substituted by a halogen atom or by a methyl radical in the 2- or 3- position, - the R" symbols are identical and represent hydrogen atoms or together form a bond, - the R3 symbol represents a halogen atom or a hydroxyl radical and the R4 symbol represents a hydrogen atom or, simultaneously with R3, represents a halogen atom, - the R'3 symbol represents a phenyl radical optionally substituted in the 2-position by an alkyl or alkyloxy radical (1 or 2 carbon atoms), and the R'4 symbol represents a fluorine atom or a hydroxyl radical, and the Rs symbol represents a hydrogen atom or else the R'4 and R5 symbols represent hydroxyl radicals, or else the R'4 symbol forms a bond with Rs, - the R"3 symbol represents a hydrogen atom and the R"4 symbol represents a fluorine atom or a hydroxyl radical, or else the R"3 symbol represents a phenyl radical optionally substituted in the 2-position by an alkyl or alkyloxy radical (1 or 2 carbon atoms), and the R"4 symbol is a hydroxyl radical, or else the R"3 and the R"4 symbols together form an oxo radical, - the n symbol is an integer from 0 to 2; it being understood that the products of general formula (Ia) to (Id) can have stereoisomeric forms which are described in more detail in European Patent Applications EP 429,366, EP 514,273 and EP 514,275 or in International Application WO 93/21155, and that the products of general formula (Ie) exist in the (3aS,7R,7aR), (3aR,7S,7aS) or (3aRS,7SR,7aSR) form, if R4 is hydroxyl and R3 is a phenyl radical, or exist in the (3aR,7S,7aS), (3aS,7R,7aR) or (3aRS,7SR,7aSR) form or their mixtures, if R3 is hydrogen and R4 is hydroxyl, or exist in the (3aR,7R,7aS), (3aS,7S,7aR) or (3aRS,7RS,7aSR) form or their mixtures, if R3 is hydrogen and R4 is fluorine, or exist in the (3aS,7aR), (3aR,7aS) or (3aRS,7aSR) form or their mixtures if R3 forms an oxo radical with R4.

By way of example, products of the 2-substituted-3-aminoquinuclidine class, derivatives of the aminoazabicycloalkane class, derivatives of the 2-substituted-3-aminopiperidine class, derivatives of the 1-azabicyclo(3. 2. 2)nonan-3-amine class and derivatives of the N-alkylquinuclidinium salt class can be products of general formula:

in their stereoisomeric forms or their mixtures, in which the ring:

represents a condensed polycyclic or monocyclic nitrogenous heterocycle having one of the structures:

When the A' ring corresponds to the general formula (IIa):: 1) R4 is a hydrogen atom, a) R1 is a radical =N-CH2-R or -N=CH-R, in which R is cycloalkyl (5 to 7 carbon atoms), norbornyl, pyrrolyl, thienyl, pyridyl, indolyl, biphenyl or phenyl which can be substituted by 1 or 2 substituents chosen from fluorine, chlorine, bromine, trifluoromethyl, alkyl or alkyloxy (1 to 3 carbon atoms), carboxyl, alkyloxycarbonyl, in which the alkyl part contains 1 to 3 carbon atoms, or benzyloxycarbonyl, and R2 is a radical Ar-CHR'- in which R' is a branched alkyl radical (3 or 4 carbon atoms), a branched alkylene radical (5 or 6 carbon atoms), a cycloalkyl radical (3 to 7 carbon atoms) or furyl, thienyl, pyridyl, indolyl, biphenyl or phenyl which can be substituted by 1 or 2 substituents chosen from fluorine, chlorine, bromine, trifluoromethyl, alkyl or alkyloxy (1 to 3 carbon atoms), carboxyl, alkyloxycarbonyl, in which the alkyl part contains 1 to 3 carbon atoms, or benzyloxycarbonyl, and Ar is a phenyl radical or else a2l) R1 is a radical -NH-CH2-R in which R is defined as above and R2 is defined as above, or a2 2) R represents a phenyl radical disubstituted by a methoxy radical and a branched butyl radical, if R2 is a benzhydryl radical, or else a23) R represents a phenyl radical trisubstituted by radicals Xl to X3 in which Xl is H, alkyl or alkyloxy (1 to 10 carbon atoms), optionally substituted by 1 to 3 fluorine atoms, and X2 and X3 are H, halogen, NO2, alkyl or alkyloxy (1 to 10 carbon atoms), optionally substitued by 1 to 3 fluorine atoms, OH, CN, phenyl, NH2, alkylamino, dialkylamino, alkylcarbamoyl, alkylcarbamoylalkyl or acylamino (in which the alkyl or acyl parts contain 1 to 6 carbons), or alkyloxyalkyl (in which the alkyl parts contain 1 to 4 carbon atoms) if R2 is either Ar-CHR'- in which R' is defined as above or represents alkyl or alkyloxy (1 to 10 carbon atoms) optionally substituted by 1 to 3 fluorine atoms, and Ar is a phenyl radical, or a phenyl, biphenyl, naphthyl, pyridyl, thienyl or furyl radical which can be mono- to trisubstituted by halogen or alkyl or alkyloxy (1 to 10 carbon atoms) optionally substituted by 1 to 3 fluorine atoms, and R3 is a hydrogen atom, or else a3) Rl is -NH-(C=Y)-R in which R is a benzopyran derivative optionally containing another heteroatom (0, S or NR' in which R' is H, alkyl or aralkyl) or a benzofuran derivative optionally substituted in the position a to the oxygen by methyl radicals, and/or substituted by an oxo or thioxo radical and/or substituted on the phenyl ring by halogen, alkyl, haloalkyl, aralkyl, alkyloxy, aralkyloxy, acyl, acyloxy, OH, NH2, CN, NO2, -NH-CO-R", S(O)a-R", -NH-SQR'1, COOR", CONR"R"', OCONR"R"', CSNR"R"' or SO2NR"R"', in which R" and R"' are H, alkyl, phenyl or aralkyl, and Y is O, S or 2H, R2 is -CHR5R6 in which Rs is thienyl or phenyl and R6 is alkyl, alkenyl, cycloalkyl, furyl, thienyl, pyridyl, indolyl, biphenyl or phenyl, and R3 is H or alkyl;; bl) Rl is defined as in a) or in a21) and R is defined as in al) or represents 2,3-dihydrobenzofuryl, alkyloxythienyl, in which the alkyl part contains 1 to 3 carbon atoms, hydroxypyridyl, quinolyl, naphthyl, alkyloxynaphthyl, in which the alkyl part contains 1 to 3 carbon atoms, 2,3-methylenedioxyphenyl, or phenyl substituted by 1 or 2 radicals chosen from the radicals mentioned above or cyano, nitro, amino, N-monoalkylamino (1 to 3 carbon atoms), allyl, hydroxyl, carboxybenzyloxy, alkyloxycarbonylbenzyloxy, in which the alkyl part contains 1 to 3 carbon atoms, carboxamido or N,N-dialkylcarboxamido, in which the alkyl parts contain 1 to 3 carbon atoms, and R' is defined as above or represents phenyl substituted by 1 or 2 radicals chosen from the radicals mentioned above or phenylalkyl, in which the alkyl part contains 1 to 3 carbon atoms, allyloxy or hydroxyl, and R3 is a hydrogen atom or an alkyl radical (1 to 4 carbon atoms) situated in the 5-position, or else b2) Rl is defined as in a23) and R2 is phenyl, biphenyl, naphthyl, pyridyl, thienyl or furyl which can be monoto trisubstituted by halogen or alkyl or alkyloxy (1 to 10 carbon atoms) optionally substituted by 1 to 3 fluorine atoms, and R3 is an alkyl radical (1 to 6 carbon atoms), or else c) Rl is a radical -NH-CH2-R in which R is phenyl, thienyl, pyridyl or furyl optionally substituted by 1 to 3 substituents chosen from fluorine, chlorine, bromine, iodine, trifluoromethyl, alkyl or alkyloxy (1 to 4 carbon atoms), R2 is a phenyl, naphthyl, thienyl, pyridyl or furyl radical optionally substituted as defined above for R, and R3 is a hydrogen atom or an alkyl radical (1 to 6 carbon atoms) situated in the 5- or 6-position, or else d) RX is a radical -NH-CH2-R in which R is phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl or pyrazolyl optionally substituted by alkyl or alkyloxy substituents, optionally carrying 1 to 3 halogens, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, dialkylamino, in which the alkyl parts can be substituted by alkylsulphinyl or alkylsulphonyl (in which the alkyl parts contain 1 to 6 carbons), sulphonamido or alkenyl (2 to 6 carbons) substituents, or in which R is phenyl substituted by halogen, alkynyl, alkylamino, N-alkyl-N (aminosulphonvl)amino or N-alkyl-N-alkanoylamino (which can be substituted by halogen on the alkylsulphonYl or alkanoyl part), alkylsulphonylamino or alkanoylamino, in which the alkyl parts can be substituted by halogen, R2 is a radical Ar-CH(Ar')- in which Ar and Ar' are cyclic radicals such as R above, which can be substituted by alkyl, alkyloxy, alkylthio, alkylsulphinyl, alkylamino (in which the alkyl parts contain 1 to 4 carbons), trifluoromethyl or trifluoromethoxy and R3 is optionally substituted (by alkyloxy, carbamoyl, -CONR.Rb, -COOH, -COORa, -CHR.ORb, CHRaNRbRc, CORAL -CONRORb, or aryl as defined for optionally substituted R, the alkyl radicals having 1 to 6 carbons and Rg, Rb and Rc being optionally substituted aryl, cycloalkyl, alkyloxy, alkyl or H) alkyl, alkenyl (2 to 6 carbons), cycloalkyl (3 to 8 carbons), or a radical as defined above for the substituents of the alkyl radical, or a radical Y-(CH2)m-CHRd-(CH2)n-NR'd-CO- in which Y is -CN, -CH2Z or -COZ (in which Z is OH, NH2, -Oalkyl, -NHalkyl or -N(alkyl)2), Rd is H, alkyl, benzyl or -(CH2)p-Y and R'd is defined as Rd or substituted (by OH, NH2, -SCH3 or SH) alkyl or 4-hydroxybenzyl or 3-indolylmethyl.

2) R3 in the 5position forms, with R4, an alkylene chain containing 3 to 5 carbon atoms if R4 is in the 6-position, or containing 2 or 3 carbon atoms if R4 is in the 7-position, or containing 2 to 4 carbon atoms if R4 is in the 8-position, or else, when R3 is in the 5-position and R4 is in the 6-position, R3 and R4 can form a chain:

or else, when RA is in the 8-position and R3 is in the 5-position, R3 and R4 can form a chain: -CH2-X-CH2- in which X is O, S, NH or > N(alkylamino), in which the alkyl part contains 1 to 3 carbon atoms.

Rl has the structure defined in lea21) and R is defined as in lea23) or represents cycloalkyl (5 to 7 carbon atoms), pyrrolyl, thienyl, pyridyl or phenyl which can be substituted by 1 to 3 substituents chosen from fluorine, chlorine, bromine, trifluoromethyl, alkyl or alkyloxy (1 to 3 carbon atoms), carboxyl, alkyloxycarbonyl, in which the alkyl part contains 1 to 3 carbon atoms, or benzyloxycarbonyl, and R2 is a radical -CHR'R" in which R' is a furyl, thienyl, pyridyl, indolyl, biphenyl or phenyl radical which can be substituted by 1 or 2 substituents chosen from halogen, alkyl or alkyloxy (1 to 10 carbon atoms), which can be substituted by 1 to 3 fluorines, carboxyl, alkyloxycarbonyl (the alkyl part containing 1 to 3 carbons) or benzyloxycarbonyl, and R" is thienyl, phenyl, halophenyl or phenyl substituted by alkyl or alkyloxy (1 to 10 carbon atoms), which can be substituted by 1 to 3 fluorines.

When the A' ring corresponds to the general formula (IIb): 1) Y is (CH2) n in which n is equal to 1 to 6 and can represent an unsaturated chain, Ri is a radical -NR'-CH2-R in which R is aryl chosen from phenyl, naphthyl, indanyl, thienyl, pyridyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl optionally substituted by one or more substituents chosen from halo, nitro, alkyl, alkyloxy, trifluoromethyl, amino, phenyl, alkylamino, formamido, acylamido, acylamidoalkyl, alkylcarbamoyl or cycloalkyl (3 to 7 carbon atoms) optionally substituted by 1 or 2 substituents as mentioned above and in which one of the carbon atoms can be replaced by N, O or S, and R' is a hydrogen atom or an alkyl radical, or Rl is defined as in lea23), R2 is a hydrogen atom, a phenylalkyl, benzhydryl or straight or branched alkyl radical or an aryl or cycloalkyl radical as defined above for R or an aryl radical such as thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl or tetrazolyl, it being possible for these various rings to be substituted by 1 or more substituents chosen from the substituents mentioned above for R, or chosen from dialkylamino, alkyloxycarbonyl, alkyloxycarbonylalkyl, acyloxy, acylalkyloxy, acyl or acylalkyl, R3 is a hydrogen atom or, when Rl is defined as in 1a23), can be a phenyl or alkyl (1 to 6 carbons) radical, or else R2 and R3 form, together with the carbon to which they are attached, a saturated, 3- to 7-membered carbocycle in which the carbon atoms can optionally be replaced by O, N or S, R5 is a radical -(CHR")m-R"' in which m is an integer from 0 to 6, it being possible for each of the CHR" units to form a double bond with the adjacent unit, and not all the R" radicals necessarily being identical, R4 and R6 can be hydrogen atoms or hydroxyl, halo, amino, alkylamino, dialkylamino, alkyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, acyloxy, acylalkyloxy, acyl or acylalkyl radicals or radicals as mentioned above for the definition of R2, with the proviso of not being able to form a ring with R5, or, if Rl is defined as in 1a23), R4 and R6 can also be oxo, hydroxyalkyl or alkyloxyalkyl, and R" and R"' are defined as R4 and R6, or, if R1 is a radical defined as in 1a23), R" can also be =N-OH and R"' a radical NHCORd, NHCH2Rd, SO2Rd or NHSO2Rd, and Rd is H, alkyl, phenylalkyl or phenyl substituted by alkyl (the alkyl parts having 1 to 6 carbons), or else 2) - Y-N(R5)- is the residue of an azabicyclic system (for example, quinuclidinyl, azabicycloheptyl or azabicyclooctyl), a) RX is a radical -X-CH2-R in which X is an oxygen or sulphur atom and R is a phenyl radical optionally substituted by 1 to 3 identical or different radicals chosen from alkyl, alkenyl or alkynyl (2 to 6 carbon atoms), halogen, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR', -SCH3, -SOCK3, -SO2CH3, -NR'R", -NR'COR", -NR'CO2R", -CO2R' or -CONR'R" in which R' and R", which are identical or different, represent hydrogen, alkyl, phenyl or trifluoromethyl, R2 represents a radical -CRgRI,Re in which R. and Rb, which are identical or different, represent phenyl or thienyl optionally substituted by halo or trifluoromethyl, or cycloalkyl, or Ra can also represent phenyl or thienyl substituted by alkyloxy or Rb can also represent benzyl, which can be substituted as defined above, and Rc is hydrogen or hydroxyl, and R31 R4 and R6 are H, or else b) RX is a radical -CHt-CHX-Ar or =CH-CHX-Ar in which Ar is a phenyl radical which can be substituted as defined above in a), X is H, OH, =O or halogen, R2 is a radical -CRaRb in which Ra and Rb, which are identical or different, represent phenyl, thienyl or benzyl optionally substituted by halo or trifluromethyl, and R3, R4 and R6 are H, or else c) Rl is a radical -NR"-CH2-R in which R is defined as in IIb 1) (for R' is H or alk) or represents alkyloxycarbonyl, formyl, hydroxymethyl, phenoxymethyl or alkyloxymethyl, R2 is defined as in IIb 1), R3, R4, R6 and R" are H, alkyl or phenyl, or else d) -Y- substituted by R4 and R6 radicals is a -CHRa=CRb(CRcRd)- chain in which one of Ra is H, hydroxymethyl, alkyl, acyloxyalkyl, alkyloxymethyl or benzyloxymethyl, Rb and Rc are H, alkyl or phenyl and Rd is methyl or hydroxymethyl, RX, R2 and R3 are defined as above in c) and Rs is H, benzyl or a radical ((CH2)Re)-Rf in which Re and Rf are defined as R' and R" below in IIg);; 3) R1 is defined as for the formula (IIb)-2a), it being understood that R in -X-CH2-R can also carry an SR', SOR' or SO2R' substituent, R2 is a phenyl, naphthyl, indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl or quinolyl radical which can be substituted by alkyl, alkyloxy, halogen or trifluoromethyl, or a benzhydryl or benzyl radical, it being possible for these radicals to be substituted by alkyl or alkyloxy (1 to 6 carbons), halogen or CF3, Y is - (CH2)n in which n is equal to 1 to 3, R3 is H, R4 and R6 are H, halogen, -CH2OR , alkyl, oxo, COOR or CONRORO in which R is H, CF3, alkyl or phenyl, and Rs is H or optionally substituted alkyl tsubstituted by COOR00, CONR R , OH, CN, COR , -NR R , C(NOH)NR00R00, CONHphenylalkyl, COCOOR00, COCONR R , optionally substituted phenyl (substituted by 1 or more alkyl, alkyloxy, halogen or CF3 substituents), or by an aromatic heterocycle which can itself be substitutedj, R is defined as above and R is H or alkyl; it being understood, except when especially mentioned, that the alkyl radicals and parts mentioned above contain from 1 to 6 carbon atoms.

When the A' ring corresponds to the general formula (IIc): x and y are integers from 0 to 4 and z is an integer from 0 to 6, it being understood that the ring containing (CH2)z can contain up to 3 double bonds and one of the (CH2)z can be replaced by 0, S or N, R1 is defined as in the case where A' is of formula (IIb)-1), R is defined as in the case where A' is of formula (IIb)-1) or represents thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl or tetrazolyl, optionally substituted by 1 or more substituents, the substituents being chosen from the radicals mentioned above for the general formula (IIb)-1) or phenyl, alkylcarbamoyl or alkylcarbamoylalkyl and R' is defined as in the case where A' is of formula (IIb)-1) or represents an alkyl radical substituted by hydroxyl, alkyloxy or fluoro, R2 and R3 are defined as for (IIb)-1), R5 is a radical ~tCHR")m~R"t in which m is an integer from 0 to 12, it being possible for each of the CKR" units to form a double or a triple bond with the adjacent unit, and not all the R" radicals necessarily being identical, or else Rs is defined as above for the formula (IIb)-1) and R4, R6, R" and R"' are defined as for the formula (IIb)-1) or can be carboxyl or carboxyalkyl radicals, it being understood, except when especially mentioned, that the alkyl radicals and parts mentioned above contain from 1 to 6 carbon atoms.

When the A' ring corresponds to the general formula (IIc'): Rl is defined as above in (inc), it being possible for the R radical of -NR-CH2-R also to carry a dialkylamino substituent, R2 is defined as above in (lIc), it being understood that the phenyl radicals of the benzhydryl can optionally be replaced by naphthyl, thienyl, furyl or pyridyl, R3 is defined as above in (IIc), or represents phenyl, R4 is defined as above in (IIc) with the exception of carrying a COOK or carboxyalkyl substituent, or can be substituted by an oxo or nitrile radical, or groups as defined for R2, R5 is defined as above in (IIc) in which R"' is hydroxyimino, or one of the groups mentioned above for R2 and R4, and R" is -NHCO-RO, -NHCH2R , -NHSO2Re or one of the groups mentioned above for R2 and R4, and RO is H, alkyl, phenyl or phenylalkyl, and m is 0 to 8, x is 0 to 2, y and z are 1 to 4 and any of the carbon atoms of (CH2)z can be substituted by the RA radical.

When the A' ring corresponds to the general formula (lId): Rl is a radical -NH-CH,-R in which R is a phenyl radical optionally substituted by 1 or 2 identical or different radicals chosen from fluorine, chlorine or bromine atoms or trifluoromethyl, alkyl, alkyloxy, carboxyl, alkyloxycarbonyl or benzoyloxy radicals, the alkyl radicals and parts containing 1 to 3 carbon atoms; R2 is a benzhydryl radical in which the phenyl rings can be substituted by 1 or 2 radicals as mentioned above.

When the A' ring corresponds to the general formula (IIe): RX is defined as above when the A' ring corresponds to the general formula (IId) and R is phenyl, thienyl, furyl or pyridyl optionally substituted by 1 to 3 substituents chosen from cyano, nitro, amino, N-alkylamino, fluorine, chlorine, bromine, trifluoromethyl, alkyl, alkyloxy, allyloxy, alkyloxycarbonyl, carboxamido or N,N-dialkylcarboxamido, the alkyl radicals and parts containing 1 to 3 carbon atoms; ; R2 is a benzhydryl radical and R3 is an alkyl (1 to 4 carbon atoms), allyl, phenylalkyl, in which the alkyl part contains 1 to 6 carbon atoms, carboxyalkyl, in which the alkyl part contains 1 to 10 carbon atoms, or alkyloxycarbonylalkyl, in which the alkyloxy part contains 1 to 4 carbon atoms and the alkyl part contains 1 to 10 carbon atoms, radical, and X is a pharmaceutically acceptable counterion, chosen from chloride, fluoride, bromide, iodide, mesylate, tosylate or trifluoromethanesulphonate.

When the A' ring corresponds to the general formula (IIf): Rl is a radical -X-NR'-X'-R in which X is alkylene, CO or a bond, X' is CO, oxoalkyene, oxo(aza)alkylene or alkylene optionally substituted by phenyl, hydroxymethyl or COOK, which can be esterified or in the amide form, or substituted in the a-position by OH, R' is H, alkyl, carbamoyl or alkanoyl or alkenoyl optionally substituted by COOH, which can be esterified or in the amide form, and R is optionally substituted aryl or optionally partially hydrogenated heterocyclyl, R2 is a radical -X"-R" in which X" is methylene, ethylene, a bond, carbonyl, optionally in the ketal or optionally etherified hydroxymethylene form, and R" is cycloalkyl or optionally substituted heterocyclyl or aryl, and R3 is aralkyl, aralkyloxyalkyl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroaralkanoyl, aralkyloxycarbonyl or arylcarbamoyl, which can be substituted, or the acyl residue of an amino acid optionally N-substituted by alkyl or carbamoylalkanoyl, and their stereoisomeric forms.

When the A' ring is replaced by the general formula (IIg): Rl is -NH-CH2-R in which R is defined as above in (IIb 1) (when R' is H), or represents alkyloxycarbonyl, formyl, hydroxymethyl, phenoxymethyl or alkyloxymethyl, R2 is H, alkyl, or phenyl optionally substituted by 1 or more halogen, alkyl or alkyloxy substituted by 1 to 3 fluorines, R3 is defined as above for R [in (IIb 1)], with the exception of representing aminoalkyl or alkylcarbamoyl, or represents alkyl or phenylalkyl or benzhydryl, which can be substituted on the phenyl by a substituent as in the definition above, R4 is -((CK2)R')-R" in which R' and R" are defined as R3 or represent OH, halogen, COOH, carboxyalkyl, alkylamino, dialkylamino, alkyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyloxy, acyloxy, acylalkyloxy or acyl and m is 0 to 12, R5 is H, alkyl, cycloalkyl (6 to 10 carbons) containing 2 condensed or bridged rings, benzyl, in which the phenyl part can be substituted by 1 or more halogen, alkyl or alkyloxy substituted by 1 to 3 fluorines, R6 is H, cycloalkyl (3 to 8 carbons), alkyl or phenyl optionally substituted by 1 or more halogen, alkyl or alkyloxy substituted by 1 to 3 fluorines, it being understood that, except when especially mentioned, the alkyl portions contain 1 to 6 carbons; and, among these products, more especially 1-N-cyclohexyl-1-phenyl-2-N' - ( (2-methoxyphenyl) methyl) - 1,2-ethanediamine.

By way of example, products of the pseudopeptide class can be especially: A) products of general formula:

in which: 1) A1 is a carbonyl radical, A2 is the residue of an amino acid, with the exception of D-Trp, which can be substituted, Rl is an alkyl, aryl, arylamino, pyridyl, pyrrolyl, pyrazolopyridyl or quinolyl radical or a radical of general formula::

in which Z is O, S or NH and X is -CR- or N, which can optionally be substituted (especially by alkyl), and --- is a single or double bond, Y is a bond or an alkylene or alkenylene radical, R2 is H or alkyl, R3 is a phenyl radical optionally substituted by hydroxyl in the 4-position or by 1 or 2 substituents chosen from alkyl, which can carry up to 3 halogens, amino, acylamino, optionally esterified carboxyalkyloxy, halogen, alkyloxy or nitro, and RX is optionally substituted alkyl, and Rs is pyridylalkyl or optionally substituted aralkyl, or else R4 and Rs are bonded together to form a condensed benzo alkylene chain, it being understood that the nature of the substituents and of the amino acid residues and the length of the carbon chains are as defined in European Patent Application EP 394,989 or EP 482,539, or else 2) At is a carbonyl or sulphonyl radical, is is a residue

in which R is a hydroxyl or alkyloxy radical, Y is a bond or an alkenylene radical, RX is an aryl radical or a radical of formula (III') in which Z is O or Nor6, R6 being H or alkyl, and

is a double bond, R2 is a hydrogen atom, R3 is a naphthyl radical, R4 is a hydrogen atom or an optionally substituted alkyl radical, and R5 is optionally substituted aralkyl, it being understood that the nature of the substituents and the length of the carbon chains are as defined in European Patent Application EP 443,132.

B) products of general formula:

in which: R1 and R2 are H, alkyl (1 to 6 carbons), cycloalkyl (3 to 7 carbons) or benzyl, B is the residue of an aromatic amino acid, and A is either a radical of structure:

in which A1 is a bond or an optionally protected tryptophan, P-naphthylalanine, leucine or 2-azabicyclo(2.2.2octane-3-carbonyl residue, A2 is an aspartic or glutamic residue and A3 is a 1,2,3, 4-tetrahydroisoquinoline-3-carbonyl, 2-azabicyclo[2.2.2.]octane-3-carbonyl, methylphenylalanine, arginine, protected arginine, 6,7 dihydroxy-1, 2,3, 4-tetrahydroisoquinoline, spinacine, 4-hydroxyproline, ss-naphthylalanine or proline residue, it being understood that the -CO-NH- bond between A1 and A2 or between A2 and B can be replaced by -CH2-NH- or -CH2-S- when A1 is a bond, or A is a peptide residue of structure: -AA-As-A6-P in which A4 and As are 2-azabicyclo(2.2.2)octane-3- carbonyl or P-naphthylalanine or As is a bond or a phenylalanine residue, A6 is a bond or tryptophan optionally protected by formyl or methyl or 2azabicyclo[2.2.2]octane-3-carbonyl, it being understood that when As and A6 are not bonds, the CO-NH bond which separates them can be replaced by -CH2-NH- or -CH2-S-, and P is H or an amine protective group such as benzyloxycarbonyl, t-butoxycarbonyl, 3-indolylcarbonyl, benzhydrylcarbonyl or fluorenylmethyloxycarbonyl, and their stereoisomeric forms.

By way of example, products of the diacylpiperazine class can be especially products of general formula:

in which X is -CH < or -N < , R1 is H, alkyl (1 to 8 carbons), phenyl or phenylalkyl substituted (on the ring) by alkyl, halogen, OH, CF3, NH2, NHalkyl, N(alkyl)2, -COOH or COOalkyl, R2 is defined as R1 or -CH2-R1 or represents cycloalkyl (3 to 7 carbons), R3 and R4 are independently phenyl as defined for Rl, alkyl (1 to 6 carbons), which can be substituted as phenyl above or substituted by SOx-alkyl, in which x is 0 to 2, or cycloalkyl (3 to 7 carbons), or else the phenyls formed by R3 and R4 can be combined at the ortho position to form a tricyclic group with X, or else XR1R2 can be -OR2, R5 and R6 are alkyl, COOR', -CH2OCOR', -CK2OK, -CH2OR", -CH2S(O)XR'', -CH2OCONR'R", -CH2CONR'R", -CONR'R", -COOR , -CH2COOR', -CH2COOR , -CONHSO2R , -CH2NR'CONR'R", or methyl substituted by amino, alkylamino or dialkylamino and R' is H or alkyl, R" is defined as R3 above with the exception of carrying an SOx-alkyl or alkyloxy substituent, or else R' and R" can, if appropriate, be joined to form a 5- or 6-membered ring which can carry another heteroatom such as O, S(O)x or N optionally substituted by alkyl, aryl or arylmethyl, RO is H, acyloxymethyl optionally substituted on the methyl as N above or arylmethyl and R"" is optionally substituted alkyl, polyfluoroalklyl, cycloalkyl, heteroaryl or aryl; or else R6 is H.

By way of example, substituted aromatic derivatives can be especially 1) products of general formula:

in which Rl and R2 are independently H, alkyl, which can be substituted (by OH, CN, CORa, COORa, CONRaRb, or NRaRb), CORa, COORa or CONRaRb in which Ra and Rb can be H, alkyl, phenyl or phenylalkyl (1 to 4 carbons) (optionally substituted on the ring by alkyl, alkyloxy, halogen or trifluoromethyl), R3 is H or alkyl, X and Y are H or together form =0, Z is O, S or NR" in which R" is H or alkyl, R' is a radical ,CHROROO in which RO is -(CH2)a-phenyl which can be substituted on the ring by 1 or more alkyl, alkenyl or alkynyl (2 to 6 carbons), halogen, CN, NO2, CF3, trimethylsilyl, ORa, SRa, 80Ra, SO2Ra, NRaRb, NRaCORb, NRaCOORb, COORa or CONRaRb in which Ra and Rb are defined as above with the exception of being substituted phenyl, a) or else RX and R2 can also be CONRaCOORb or SO2Ra, ROO is H, alkyl or optionally substituted phenyl as defined for RO, and n in R" equals 0, and R is Q-CH2- in which Q is optionally substituted phenyl, naphthyl, benzothiophenyl, benzofuryl, benzyl or indazolyl; b) or else Rl and R2 can also be Co-alkyl-NRaRb, CONRaCOORb or SO2Ra, R3 is defined as above for the general formula (V) or represents alkenyl, X and Y are defined as for the general formula (V) or Y is OH or alkyloxy or X and Y together form =NOR", Z is a -CH2- or -CH= radical, RDO is H or forms a double bond with Z and n in R" equals 0, and R is Q-CH2- in which Q is phenyl substituted by 1 or more halogens, or optionally substituted naphthyl, indolyl, benzothiophenyl, benzofuryl, benzyl or fluorenyl; c) or else Rl and R2 can also be alkyl substituted by CO-alkyl-NRaRb or CON(Ra)alkylCONRaRb, phenyl (optionally substituted by alkyl, alkyloxy, halogen or trifluoromethyl), alkenyl (2 to 6 carbons), haloacyl, CO-alkyl-NRaRb or CON(Ra)alkylCONRaRb, or Rl and R2 together form an alkylene radical containing 4 or 5 carbons in which a methylene radical can be replaced by O or NRx in which Rx is H or alkyl, R"" is H, alkyl or optionally substituted phenyl as defined for R", and n in R" is 0 to 2, and R is a group::

in which W is a bond, 0, S, -(CH2)2-, -CH=CH-, or NR" and R4 and R3 are alkyl, alkenyl or alkynyl (2 to 6 carbons), halogen, CN, NO2, CF3, trimethylsilyl, ORa, SRa, SORa, SO2Ra, NRaRb, NRaCORb, NRaCOORb, COORa or CONRaRb in which Ra and Rb are defined as above with the exception of being substituted phenyl and m and m' ranging from 0 to 4; d) or else RX and R2 can also be alkyl substituted by CO-alkyl-NRaRb, CON(R'a)alkylORa or CON(R'a)alkylCONRaRb, phenyl (optionally substituted by alkyl, alkyloxy, halogen or trifluoromethyl), alkenyl (2 to 6 carbons), alkynyl (2 to 6 carbons), SO2Ra, haloacyl, CO-alkyl-NRaRb or CON(Ra)alkylCONRaRb, or Rl and R2 together form an alkylene radical containing 4 or 5 carbons in which a methylene radical can be replaced by O or NRx in which Rx is H or alkyl and Ra and Rb are defined as above for the general formula (V) or together form a chain as defined for RX and R2 and R'a is defined as Ra for the general formula (V), R3 is defined as above for the general formula (V) or represents alkenyl, ROO is H and n in R" is o to 2, and R is -CR6R7R8 or -CH2-CR6RzR8 in which R6 is H or OH and R7 and R8 are substituted benzyl or phenyl, or cycloalkyl or cycloalkylmethyl (5 to 7 carbons); e) or else RX and R2 can also be defined as above in c) with the exception of simultaneously representing H, X and Y are defined as for the general formula (V) or can also be alkyl or alkenyl (2 to 6 carbons), Z is defined as for the general formula (V) with the exception of being NR", ROO and n in RO are defined as above in c) and R is optionally substituted heteroaryl, naphthyl or phenyl; or else 2) products of general formula:

in which Z is O, S or NR" or CR4Rs in which R1', R4 and R5 are H, alkyl or optionally substituted phenyl or phenylalkyl (in which the alkyl part contains 1 to 4 carbons), or else R" is -COR6, -COOR6 or -CONR4Rs and R6 is alkyl or optionally substituted phenyl or phenylalkyl (in which the alkyl part contains 1 to 4 carbons), R' is defined as for the formula (V), R3 and R is defined as for the general formula (V) in b), and ROO e is H and n in RO is 0 to 3; it being understood that, except when especially mentioned, the alkyl portions contain 1 to 6 carbons.

By way of example, antagonists of NR1 receptors of the dialkylenepiperidino derivatives class can be products of general formula:

in which: Ar is optionally mono- or polysubstituted (by halogen, alkyl or alkyloxy (1 to 3 carbon atoms), OH or trifluoromethyl) phenyl, or thienyl, pyridyl or naphthyl which can be substituted by halogen, or benzothienyl or indolyl, and R is a hydrogen atom or an alkyl radical (1 to 6 carbon atoms), or an aminoalkyl radical of structure -(CH2)E-NH2 in which n is equal to 2 to 6, T is a -CO-, -CO-O-, -CO-NH- or -CS-NH- group, and T' is a bond except if Z' is a hydrogen atom, or represents a -CH2-, -CO-, -CH2-O- or -CO-O- radical, Z and Z', which are identical or different, are H, straight or branched alkyl (1 to 6 carbon atoms), phenylalkyl, in which the alkyl part contains 1 to 3 carbon atoms, optionally mono- or polysubstituted on the phenyl by halogen, OH, alkyl or alkyloxy (1 to 4 carbon atoms), pyridylalkyl or naphthylalkyl or pyridylthioalkyl or 1-methyl-2-imidazolylthioalkyl, in which the alkyl part contains 1 to 3 carbon atoms, styryl, 1-oxo-3-phenyl-2-indanyl, or an unsubstituted, mono- or polysubstituted heteroaromatic or aromatic group or an a-hydroxybenzyl group or an a-alkylbenzyl group in which the alkyl part contains 1 to 3 carbon atoms.

Products of the substituted piperidine quaternary salts class can be especially products of general formula:

in which: Y is Y'-CXX'-CX" or Y'-(CH,),-CXO in which Y' is phenyl, which can be substituted (by 1 or more H, halogen, OH, alkyloxy, alkyl or CF3), cycloalkyl, pyridyl or thienyl, X is H if X forms a bond with X", or else X and X' form oxo and X" is H, x is 0 and XO is H or else x is 0 or 1 and XO is OH, alkyloxy, acyloxy, carboxyl, carbalkoxy, CN, -NH-CO-alkyl, mercapto or alkylthio, or else X forms a bond with the carbon atom of the piperidine, Q is alkyl or benzyl, R' is H and R is H or alkyl, or else Y is Y'-CXO in which Y' is defined as above, XO forms an ethylenyl radical with Q and R' and R form, together with the atoms to which they are attached, a piperidino radical, A is a Cr, Bur', I, acetate, methanesulphonate or p-toluenesulphonate anion, Ar is defined as for the general formula (VI) with the exception of substituted naphthyl or pyridyl, or represents N-alkylindolyl, T is C=O, CO-O, -(C=O)-NH- or -(C=S)-NH-, and Z is defined as for the general formula (VI) or represents a-hydroxyalkylbenzyl or phenyl substituted by CF3, naphthyl substituted by substituents as listed for phenyl or an optionally substituted mono-, di- or tricyclic heteroaromatic or aromatic group and m is 2 or 3; and, among these quaternary salts, especially the product of formula:

As non-limiting examples, antagonists of NK2 receptors can be especially derivatives of the arylalkylamine class, the a-substituted polypeptide class or of the class of piperidine derivatives, and the like.

By way of example, antagonists of NK2 receptors of the arylalkylamine class can be products of general formula:

in which: 1) Y is a group > N-CXX'-Ar', > CH-CXX'-Ar' or > C=CX-Ar' in which X is H and X' is H or OH or X and X' together form an oxo radical or a dialkylaminoalkyloxyimino radical in which the alkyl parts contain 1 to 4 carbon atoms and the alkyloxy part contains 2 or 3 carbon atoms, Ar and Ar' are independently thienyl or phenyl, optionally mono- or polysubstituted (by halogen, alkyl or alkyloxy (1 to 3 carbon atoms), trifluoromethyl, hydroxyl or methylenedioxy) or imidazolyl, or else Ar can be benzothienyl or naphthyl optionally substituted by halogen, biphenyl or indolyl, which can carry a benzyl group on the nitrogen atom, R' is a hydrogen atom, an alkyl radical (1 to 4 carbon atoms), or an alkyl radical (2 or 3 carbon atoms) substituted by piperidino, 4-benzylpiperidino or dialkylamino in which the alkyl parts contain 1 to 4 carbon atoms, R and T are defined as for the general formula (VI) and Z is H, straight or branched alkyl (1 to 6 carbon atoms), phenylalkyl in which the alkyl part contains 1 to 3 carbon atoms, optionally mono- or polysubstituted on the phenyl by halogen, OH, alkyl or alkyloxy (1 to 4 carbon atoms), pyridylalkyl or naphthylalkyl or pyridylthioalkyl or 1-methyl-2-imidaZolylthioalkyl in which the alkyl part contains 1 to 3 carbon atoms, styryl, 1-oxo-3-phenyl-2-indanyl or an unsubstituted, mono- or polysubstituted heteroaromatic or aromatic group, and m is an integer from 1 to 3, p is equal to 1 and q is equal to o, or else 2) Y is a group > N-Ar' in which Ar' is a phenyl radical which can be substituted one or more times (by halogen, OH, alkyloxy or alkyl (1 to 4 carbon atoms) or trifluoromethyl), pyrimidinyl or pyridyl, a > N-cycloalkyl group (3 to 7 carbon atoms), or else a > CX-(CH2)x-Ar' group in which Ar' is defined as above with the exception of representing pyrimidinyl, or represents thienyl, X is OH, alkyloxy (1 to 4 carbon atoms), hydroxyalkyl or acyloxy in which the alkyl part contains 1 to 3 carbon atoms, phenacyloxy, carboxyl, carbalkoxy (1 to 4 carbon atoms), cyano, aminoalkylene (1 to 3 carbon atoms), amino, alkylamino or dialkylamino in which the alkyl parts contain 1 to 4 carbon atoms, acylamino (2 to 7 carbon atoms), acylaminoalkyl in which the alkyl parts contain 1 to 3 carbon atoms, acyl, -SH or alkylthio in which the alkyl part contains 1 to 4 carbon atoms and x is o or 1, or else a =C-(CH2)x-Ar' group in which Ar' is defined as above, T is defined as in 1), and Z is defined as in 1) with the exception of representing 1-methyl-2-imidazolylthioalkyl or 1-oxo-3-phenyl-2indanyl, or represents phenylalkyl substituted by trifluoromethyl or naphthylalkyl in which the alkyl part contains 1 to 3 carbon atoms and optionally substituted on the naphthyl ring by a halogen atom or by a trifluoromethyl, OH, alkyl or alkyloxy (1 to 4 carbon atoms) radical, Ar is thienyl or phenyl, optionally mono- or polysubstituted (by halogen, alkyl or alkyloxy (1 to 4 carbon atoms), or trifluoromethyl) or benzothienyl, naphthyl or indolyl, which can carry an alkyl group (1 to 3 carbon atoms) on the nitrogen atom, R' is a hydrogen atom, R is a hydrogen atom or an alkyl radical (1 to 6 carbon atoms), and m is an integer equal to 2 or 3, p is equal to 1 and q is equal to 0, or else 3) Y is a > N-Ar' or > N-CH2-Ar' group in which Ar' is defined as above in 2), or else a > CX-(CH2)x-Ar' group as defined above, X being OH, alkyloxy, acyloxy or carbalkoxy (1 to 4 carbon atoms), carboxyl, cyano, optionally mono- or disubstituted (by alkyl, hydroxyalkyl or acyl (1 to 4 carbon atoms)) amino, pyrrolidino, piperidino, or morpholino, -SH or alkylthio in which the alkyl part contains 1 to 4 carbon atoms and x is 0 or 1, or else a =C-(CH2)x-Ar' group in which Ar' is defined as above, Ar is defined as above in 2) with the exception of representing a substituted indolyl radical, R and R' together form a

chain in which Q is an oxygen atom or 2 hydrogen atoms, T is -CO- or -CH2- and Z is phenyl or naphthyl optionally mono- or polysubstituted by halogen, trifluoromethyl, OH or alkyl (1 to 4 carbon atoms), or by alkyloxy (1 to 4 carbons) when Z is phenyl, pyridyl, thienyl, indolyl, quinolyl, benzothienyl or imidazolyl, or an unsubstituted, mono- or polysubstituted heteroaromatic or aromatic group, or, when T is CO, ~(CH2)q~Z can be benzyl in which the methyl radical is substituted by OH, alkyl or alkyloxy (1 to 4 carbons) or substituted on the ring by halogen, trifluoromethyl, OH, alkyl or alkyloxy (1 to 4 carbons), and m is an integer equal to 2 or 3, p is equal to 1 or 2, n is equal to 0 to 3 and q is equal to 0 to 3, it being understood that if p = 2 : n = 1 and Q represents 2H; or else 4) Y is a group Ar'-X- in which Ar' represents thienyl or phenyl, optionally mono- or polysubstituted (by halogen, alkyl or alkyloxy (1 to 3 carbons), trifluoromethyl, hydroxyl or methylenedioxy), pyridyl or imidazolyl, optionally substituted by an alkyl radical, and X is an oxygen or sulphur atom or a sulphonyl, sulphinyl, -NH-, > N-CO-Alk, sN-Alk or > N-Alk-NX1X2 radical in which Alk is alkyl or alkylene (1 to 3 carbons) and Xl and X2 are H or alkyl (1 to 3 carbons) or form, with the nitrogen atom, a piperidine, pyrrolidine or morpholine ring, Rx is a hydrogen atom, an alkyl radical (1 to 4 carbons) or an aminoalkyl radical in which the straight-chain alkyl part contains 2 or 3 carbon atoms and the amino group can be dialkylamino in which the alkyl parts contain 1 to 4 carbon atoms, piperidino or 4-benzylpiperidino, Ar, R and T are defined as in 1), Z is defined as above in 1) or represents a-hydroxybenzyl or a-alkylbenzyl in which the alkyl part contains 1 to 3 carbon atoms, and m, p and q are defined as above in 2), or else 5) Y is a group > CX-(CH2)x-Ar' in which Ar' is thienyl or phenyl, optionally mono- or polysubstituted (by halogen, alkyl or alkyloxy (1 to 4 carbons), trifluoromethyl or hydroxyl) or pyridyl, x is 0 or 1, and X is -NH-CO-alkyl in which the alkyl part contains 1 to 6 carbons, m is 2 or 3, p is 1 and q is equal to 0, Ar, T and Z are defined as in 2), R' is H and R is H or alkyl; and, among these products, the product of Example 2 mentioned below, which is a specific antagonist of NK2 receptors, is described more particularly by X.

Emonds-Alt et al., Life Science, 50, PL 100 to PL 106 (1992).

By way of example, antagonists of NK2 receptors of the a-substituted polypeptide class can be products of general formula:

in which Rl is a hydrogen atom or an N-terminal group consisting of o to 4 amino acids, R2 is an amino acid side chain, apart from glycine, R3 is a C-terminal group consisting of 0 to 4 amino acids or an OH or OR radical in which R is a straight or branched alkyl or cycloalkyl radical containing 1 to 6 carbon atoms, R4 is an amino acid side chain, apart from glycine, or a -CH=CH2, -CHECH, -CH2-CH=CH2, -CH,-CHECH, -CH2-Ar, -CH2 OR, -CH2-OAr, -(CH2)DCO2R or -CH2-NRsRó radical, n being an integer from 0 to 3, R being H or a lower alkyl radical and Ar being an unsubstituted or substituted, mono- or polycyclic, aromatic or hydroaromatic heterocycle or carbocycle, it being understood that R1 and R2 cannot comprise more than 4 amino acid residues in total.

By way of example, antagonists of NK2 receptors of the class of piperidine derivatives can be products of general formula:

in which Rl is phenyl optionally substituted by 1 or 2 alkyl, alkyloxy, CF3 or halogen, R2 is H, OH or alkyl, 4 is H or alkyl, R4 is H, alkyl or alkyloxy, and R5 is H, alkyl, CF3, CN or halogen and n is 0 to 2, the alkyl radicals having 1 to 4 carbons; and, among these products, more especially 1-(2-(5- fluoro-1K-indol-3-yl) ethyl) -4 ((phenylsulphinyl) methyl) -4-piperidinol.

The products of general formulae (I) to (X) can be prepared according to the methods described in Patent Applications EP 429,366, EP 514,273, EP 514,275 WO 90/05525, WO 90/05729, WO 91/18899, WO 91/09844, WO 92/01688, WO 92/06079, WO 92/15585, WO 92/12151, WO 92/20661, WO 92/20676, WO 92/21677, WO 93/00330, WO 93/00331, WO 93/01159, WO 93/01169, WO 93/01165, WO 93/01170, WO 93/06099, WO 93/09116, WO 93/10073, WO 93/18023, WO 93/19064, WO 93/21155, WO 93/21181, WO 93/23380, EP 499,313, EP 394,989, EP 443,132, EP 482,539, EP 517,589, EP 520,555, EP 522,808, EP 528,495, EP 532,456, EP 533,280, EP 536,817, EP 545,478, EP 559,538, WO 91/18878, WO 92/17449, EP 428,434, EP 474,561, EP 512,901, EP 512,902, EP 515,240, FR 2,678,267, WO 92/19254, WO 93/14084 or WO 93/21155 or by analogy with these methods.

The thiapyranopyrrole derivative of general formula:

in which the R, R"3 and R"4 radicals are defined as above, used as starting material for the preparation of the products in which the A-B bicycle corresponds to the general formula (Ie), can be prepared according to the following methods: - when R"4 is a fluorine atom, the product of general formula (I'e) can be prepared by fluorination of a thiapyranopyrrole derivative of general formula:

in which R is defined as above and R6 is a protective radical, and then removal of the R6 radical.

The R6 protective radical can be any amino protective group which is compatible with the reaction and whose introduction and removal does not detrimentally affect the remainder of the molecule.

Invention may be made, by way of example, of alkyloxycarbonyl, benzyloxycarbonyl, optionally substituted benzyl, formyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, vinyloxycarbonyl, phenoxycarbonyl, 1-chloroethoxycarbonyl or chlorocarbonyl groups.

The reaction is advantageously carried out using a fluorinating agent such as a sulphur fluoride tmorpholinosulphur trifluoride, sulphur tetrafluoride (J. Org. Chem., 40, 3808 (1975)), diethylaminosulphur trifluoride (Tetrahedron, 44, 2875 (1988)), phenylsulphur trifluoride (J. Am. Chem. Soc., 84, 3058 (1962)), such as selenium tetrafluoride (J. Am. Chem.

Soc., 96, 925 (1974)) or such as tetrafluorophenylphosphorane (Tet. Let., 907 (1973)), the reaction being carried out in an organic solvent such as a chlorinated solvent (dichloromethane or dichloroethane, for example) at a temperature between -30 and 300C. The subsequent removal of the R6 protective radical is carried out according to the usual methods, especially according to the methods described by T.W. Greene, Protective Groups in organic Synthesis, A. Wiley Interscience Publication (1981), or by XcOmie, Protective Groups in Organic Chemistry, Plenum Press (1973).

- when R"3 is a phenyl radical optionally substituted in the 2-position by an alkyl or alkyloxy radical and R"4 is a hydroxyl radical, the product of general formula (I'e) can be obtained by reacting an organometallic compound of general formula: R"3-M (I"'e) in which R"3 is defined as above and M represents lithium, cerium or a radical MgX in which X is a halogen atom, with the corresponding thiapyranopyrrolone derivative of general formula:

in which R and R6 are defined as above, and then optionally removal of the R6 protective radical.

The reaction is carried out in anhydrous medium, under the usual conditions for the reaction of organometallic compounds with a ketone, which do not affect the remainder of the molecule, especially in an ether (for example, tetrahydrofuran or ethyl ether), optionally in the presence of anhydrous cerium chloride, at a temperature between -78 and 300C.

The thiapyranopyrrole derivatives of general formula (I'e) or (I"e) in which R"3 is a hydrogen atom and R"4 is a hydroxyl radical can be obtained by respectively reducing the derivative of general formula (ire) or the corresponding thiapyranopyrrolone derivative of general formula (I'e) for which R"3 and Rw4 together form an oxo radical. The reduction is advantageously carried out using an alkali metal borohydride (sodium borohydride, lithium tri-secbutylborohydride) in a solvent such as an alcohol (methanol or ethanol, for example) or an ether (tetrahydrofuran) in basic medium, at a temperature between -20 and 500C.

The thiapyranopyrrolone derivative of general formula (I'e) in which R"3 and R"4 together form an oxo radical or the thiapyranopyrrolone derivative of general formula (I1Ve) can be prepared from the thiapyranone of general formula:

in which R is defined as above, and then introducing the R6 protective radical if it is desired to obtain a product of general formula (liVe).

The potentialization of the combinations of antagonists of NK1 receptors and of antagonists of NK2 receptors was revealed in the following way: Capsaicin, administered at a low dose, causes the release of various neuropeptides, especially substance P and neurokinin A in the primary afferent fibres of various peripheral tissues.

Antagonists of substance P are known to block the effects of an agonist of NK1 receptors and antagonists of neurokinin A are known to block the effects of an agonist of NK2 receptors. However, when these agonists are replaced by capsaicin, the action usually observed with agonists becomes extremely weak or disappears completely.

It has been shown, in an identical test, that the administration of a combination of antagonist products of substance P and antagonists of neurokinin A blocks the effects of capsaicin, or, in other terms, causes the reappearance of the action usually observed with NK1 and NK2 agonists.

METHODS: I) INHIBITION OF THE CONTRACTION OF THE RAT BLADDER, IN VIVO, CAUSED BY TOPICAL ADMINIGTRATION OF CAPSAICIN PRINCIPLE The local application of capsaicin on the rat bladder, in vivo, triggers a dose-dependent contraction due mainly to release of substance P and neurokinin A acting respectively on NK1 and NK2 receptors.

Pretreatment with an NK1 or NK2 antagonist, or their combination, should thus inhibit the submaximal contraction caused by capsaicin.

TECHNIQUE The animals used are female Sprague-Dawley rats weighing from 210 to 260 g which are anaesthetized by ethyl carbamate and whose rectal temperature is maintained at 380C. Pretreatment is carried out with chlorisondamine (Ecolids), 0.5 mg/kg i.v., in order to suppress any spontaneous or reflex vesical contraction.

The intravesical pressure is continuously measured by virtue of a catheter introduced urethrally and connected to a strain gauge pressure sensor itself connected to an amplifier and to a graph recorder. This pressure is adjusted to a value of 3 mm of mercury at the beginning of the experiment by filling with 0.98 NaCl solution. A low laparotomy is carried out in order to access the bladder.

Each antagonist (NK1 or NK2) or their combination is injected into a jugular vein 40 minutes after administration of chlorisondamine.

Five minutes after treatment with the antagonist(s), a capsaicin solution (250 ng in 10 ml) is applied on the rounded surface of the bladder for 3 minutes, by virtue of its deposition on a small piece of filter paper placed beforehand on this region. The 8 of inhibition by the antagonist(s) of the contraction due to capsaicin is calculated by comparing the rise in the intravesical pressure observed in the treated batches with respect to the capsaicin control batch.

RESULTS: The products studied are denoted as defined below: - Antagonist of NK1 receptors: Product 1: (3aR,7aR)-2-(1-imino-2-(2 methoxyphenyl)ethyl]-7,7-diphenylperhydroisoindol- 4-one:

- Antagonist of NK2 receptors: Product 2: N-methyl-N-(4- (4-phenyl-4- acetamidopiperidinyl)-2-(3,4-dichlorophenyl)- butyl]benzamide::

Treatment intravesical Inhibition with pressure respect to the (mm of Hg) control batch capsaicin controls 5.5 + 0.9 250 ng topically Product 1 5.3 + 1.1 (not 4 % significant) Product 2 5.0 t 0.6 (not 9 % significant) Product 1 + 1.4 + 0.2 74 8 Product 2 (P < 0.001) Table I Product 1 and Product 2, administered alone at a dose of 0.5 mg/kg intravenously, did not inhibit the contraction caused by capsaicin. In contrast, their combination markedly reduced (74 %) the action of capsaicin in an entirely significant way (P < 0.001).

II) INHIBITION OF BRONCHOSPASM CAUSED BY CAPSAICIN ADXINISTERED INTRAVENOUSLY TO GUINEA PIGS PRINCIPLE The i.v. injection of capsaicin in guinea pigs triggers a bronchospasm due mainly to release of substance P and neurokinin A acting respectively on NK1 and NK2 receptors. Pretreatment with an NK1 or NK2 antagonist, or their combination, should thus inhibit this bronchospasm.

TECHNIQUE The animals used are female Hartley guinea pigs weighing from 330 to 480 g anaesthetized with ethyl carbamate and whose rectal temperature is maintained at 370C. After starting up artificial respiration (0.1 ml of air/100 g of body weight, 50 insufflations/min), the animals receive a curariform (pancuronium bromide, 0.8 mg/kg i.v.) to improve ventilation, and then chlorisondamine (Ecolid), 0.5 mg/kg i.v., in order to block autonomous nervous system reflexes. The insufflation pressure is continuously measured in a side tube placed on the tracheal cannula, by virtue of a strain gauge pressure sensor connected to an amplifier and to a graph recorder.

Capsaicin (2.5 mg/kg i.v. bolus) is injected 25 minutes before, and then 5 minutes after, i.v.

treatment with the antagonist (NK1 or NK2) or their combination. All these injections are carried out in a jugular vein.

The % of inhibition by the antagonist(s) of bronchospasm due to capsaicin is calculated by comparing the increase in the maximum intracheal insufflation pressure observed at the second capsaicin injection with respect to the first.

RESULTS The products studied are denoted as defined below: - Antagonists of NK1 receptors: Product 3: (3aS,4S,7aS)-7,7-diphenyl-4-(2 methoxyphenyl)-2-[(s)-2-(2-methoxyphenyl)pro- pionyl) perhydroisoindol-4-ol

Product 4: 3-C(2-methoxyphenyl)methylamino-2- phenylpiperidine

- Antagonist of NK2 receptors: Product 2: N-methyl-N-[4-(4-phenyl-4-acetamido- piperidinyl)-2-(3,4-dichlorophenyl)butyl]- benzamide.

Insufflation pressure A Variation in % Treatment due to capsaicin (mm of Hg) of the response to Before After capsaicin treatment treatment before/after treatment Capsaicin con trols 26 S 5 27 + 4 (not + 4 % 250 ng intra- significant) venously Product 3 26 + 3 25 + 2 (not - 4 % ~ significant) Product 2 27 t 3 26 + 5 (not - 4 % significant) Products 2 + 3 34 + 3 11 | 2 - 68 % (P < 0.001) Product 4 25 + 5 28 + 7 (not + 13 % significant) Product 2 27 t 3 26 + 5 (not - 4 % significant) Products 2 + 4 23+ 6 0.5 + 0.2 - 98 % (P < 0.001) Table II Products 3 and 4, administered alone at a dose of 1 mg/kg intravenously, did not inhibit bronchospasm caused by capsaicin. It is likewise the case for Product 2 (NK2 antagonist) at the same dose.

In contrast, the combination of Products 2 and 3 reduced bronchospasm by 68 % and the combination of Products 2 and 4 reduced bronchospasm by 98 %.

Thus, as shown in Tables I and II, none of the antagonists administered alone is capable of inhibiting the effects of capsaicin. On the other hand, the combination of antagonists of NK1 and NK2 receptors powerfully antagonizes the spasmogenic effects of capsaicin on the bladder and bronchial tubes.

The following example illustrates the preparation of products which can be used in the combination.

Preparation of Product 3 0.025 g of 1-hydroxybenzotriazole, 0.38 g of (S) -2- (2-methoxyphenyl)propionic acid and 0.32 cm3 of diisopropylethylamine are added to a suspension of 0.8 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2methoxyphenyl)perhydroisoindol-4-ol hydrochloride in 60 cm3 of dry dichloromethane, this solution is then cooled to +5"C and a suspension of 0.43 g of 1-E3 (dimethylamino)propyl)-3-ethylcarbodiimide in 10 cm3 of dry dichloromethane is rapidly added. The reaction mixture is stirred for 2 hours at +5"C and for 2 hours at room temperature, washed with 20 cm3 of water, then washed with 20 cm3 of a saturated aqueous sodium chloride solution (twice), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of Merck silica gel (particle size 0.04-0.06 mm, diameter 2.8 cm, height 20 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 25 cm3 fractions. Fractions 9 to 15 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile and diisopropyl ether. There is obtained 0.17 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2 methoxyphenyl)-2-[(s)-2-(2-methoxyphenyl)propionyla- perhydroisoindol-4-ol in the form of white crystals melting at 244"C.

(3aS,4S,7aS)-7,7-Diphenyl-4-(2- methoxyphenyl)perhydroisoindol-4-ol hydrochloride can be prepared in the following way: A solution of 100 cm3 of a 5.2N solution of hydrochloric acid in dioxane is added at room temperature to a solution of 7.63 g of (3aS,4S,7aS) 7,7-diphenyl-4- (2-methoxyphenyl) -2- (tert- butoxycarbonyl)perhydroisoindol-4-ol in 66 cm3 of dioxane. The reaction mixture is stirred for 1 hour at this temperature and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is washed with acetonitrile, filtered off and then dried. There are obtained 4.88 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2methoxyphenyl)perhydroisoindol-4-ol hydrochloride in the form of white crystals melting at 2710C (Maquenne block).

(3aS,4S,7aS)-7,7-Diphenyl-4-(2- methoxyphenyl)-2-(tert-butoxycarbonyl)perhydroisoindol4-ol can be prepared in the following way: A suspension of 2-methoxyphenylmagnesium bromide (prepared from 75.3 g of 2-bromoanisole and 9.8 g of magnesium) in 100 cm3 of dry tetrahydrofuran is added dropwise at room temperature with stirring to a suspension of 20 g of (3aS,7aS)-7,7-diphenyl-2-(tertbutoxycarbonyl)perhydroisoindol-4-one and 31.6 g of anhydrous cerium chloride in 250 cm3 of dry tetrahydrofuran.The reaction mixture is stirred at room temperature for 24 hours, treated with 400 cm3 of a saturated aqueous ammonium chloride solution, diluted with 200 cm3 of ethyl acetate, washed with 300 cm3 of water (twice) and then with 300 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of Merck silica gel (particle size 0.04-0.06 mm, diameter of 5.8 cm, height 26.5 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 100 cm3 fractions. Fractions 9 to 29 are combined and concentrated to dryness under reduced pressure (2.7 kPa).There are obtained 17.82 g of (3aS,4S,7aS)- 7, 7-diphenyl-4- (2-methoxyphenyl) -2- (tert- butoxycarbonyl)perhydroisoindol-4-ol in the form of a white foam.

Proton NMR spectrum (d6-DMSO): 1.36 (s, 9H, -C(CH3)3), 1.54 (dmt, J = 14, 1H, equatorial H of the -CH2- in the 5-position), 2.3 (dmt, J = 14, 1H, equatorial H of the -CR2- in the 6-position), 2.34 (td, J = 14 and 2.5, 1H, axial H of the -CH2- in the 5-position), 3.07 (td, J = 14 and 2.5, axial H of the -CR2- in the 6-position), 3.49 (s, 3H, -OCR3), 2.6 to 3.6 (mt, other -CR2- and -CH), 6.85 to 7.7 (mt, 14H, aromatic protons).

(3aS,7aS)-7,7-Diphenyl-2-(tertbutoxycarbonyl)perhydroisoindol-4-one can be obtained in the following way: 34.3 cm3 of triethylamine, 58.6 g of di-tertbutyl dicarbonate and then 2.98 g of 4-dimethylaminopyridine are added at room temperature with stirring to a suspension of 80 g of (3aS,7aS)-7,7-diphenylperhydroisoindol-4-one hydrochloride in 400 cm3 of dry dichloromethane.The reaction mixture is stirred at room temperature for 24 hours, washed with 100 cm3 of an aqueous citric acid solution, then with 100 cm3 of an aqueous sodium hydrogencarbonate solution, then with 100 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 spa). There are obtained 106.5 g of (3aS,7aS)-7,7-diphenyl-2-(tertbutoxycarbonyl)perhydroisoindol-4-one in the form of an orange foam.

Proton NMR spectrum (dG-DMSO): 1.4 (s, 9H, -C(CH3)3), 2.11 (td, J = 15 and 7.5, 1H, axial H of the -CR2- in the 5-position), 2.3 (dt, J = 15 and 3.5, 1H, equatorial H of the -CR2- in the 5-position), 2.75 to 2.9 (mt, 4H, -CR2- in the 6-position and -CR2- in the 1-position), 3.26 (dd, J = 7.5 and 7, 1H -CH in the 3a-position), 3.35 (dd, J = 11 and 7, 1H, one H of the -CR2- in the 3-position), 3.97 (mt, H, -CH in the 7a-position), 4.1 (d, J = 11, 1H, the other H of the -CR2- in the 3-position), 7.1 to 7.7 (mt, 10H, aromatic protons).

(3aS,7aS)-7,7-Diphenylperhydroisoindol-4-one hydrochloride can be obtained in the following way: 50 cm3 of 4N aqueous sodium hydroxide are added slowly, with stirring, to a suspension of 20 g of (3aRS,7aRS)-7,7-diphenylperhydroisoindol-4-one hydrochloride in 250 cm3 of ethyl acetate; stirring is continued until the starting material has disappeared.

The organic solution is washed with 100 cm3 of distilled water and with 100 cm3 of a saturated sodium chloride solution, dried over magnesium sulphate and filtered. A solution of 9.3 g of D-(-)-mandelic acid in 50 cm3 of ethyl acetate is added with stirring to the solution thus obtained. The crystals formed are filtered off, washed with 50 cm3 of ethyl acetate (twice) and dried.

The crystals are taken up in a solution of 220 cm3 of acetonitrile and 60 cm3 of distilled water and the mixture is brought to reflux with stirring for 15 minutes; the crystals formed are filtered and again crystallized from a mixture of 100 cm3 of acetonitrile and 35 cm3 of distilled water. There are obtained 6.4 g of (3aS,7aS)-7,7-diphenylperhydroisoindol-4-one D-mandelate.

50 cm3 of 1N aqueous sodium hydroxide are added to 6.4 g of (3aS,7aS)-7,7diphenylperhydroisoindol-4-one D-mandelate in solution in 100 cm3 of ethyl acetate; the reaction mixture is stirred at room temperature until the starting material has disappeared; the organic solution is washed with 50 cm3 of distilled water, with 50 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered; it is acidified with stirring by addition of 2 cm3 of a 9N solution of hydrochloric acid in ethanol; the crystals obtained are filtered off, washed with ethyl acetate and then with isopropyl ether and dried. There are obtained 4.24 g of (3aS,7aS)-7,7diphenylperhydroisoindol-4-one hydrochloride in the form of white crystals melting at 2700C with decomposition.

(S) -2- (2-Methoxyphenyl)propionic acid can be prepared, by analogy with the methods described by D.A. Evans et al., Tetrahedron, 44, 5525, (1988), according to the following procedure: 1.52 g of lithium hydroxide are added to a solution, cooled to +50C, of 4.1 g of (4S,5S)-4-methyl 5-phenyl-3-( (S) -2- (2-methoxyphenyl)propionyl)- oxazolidin-2-one in 60 cm3 of tetrahydrofuran and 30 cm3 of water. The reaction mixture is stirred for 3 hours at this temperature and then, after returning to room temperature, ethyl acetate is added, separation is carried out by settling, the aqueous phase is acidified with a 1N aqueous hydrochloric acid solution, extracted with ethyl acetate, the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa).The solid obtained is recrystallized from hexane, filtered off and dried.

There is obtained 0.4 g of (S)-2-(2-methoxyphenyl) prop ironic acid in the form of white crystals melting at 102 OC. à)20 = +84.60 (c=1, CHCl3).

(4S,5S)-4-Methyl-5-phenyl-3-t(S)-2-(2- methoxyphenyl) propionyl) oxazolidin-2-one can be obtained in the following way: 19.1 g of sodium 1,1,1,3,3,3-hexamethyldisilazanate are added to a solution, cooled to -500C, of 10 g of (4S,5S)-4-methyl-5-phenyl-3-((2- methoxyphenyl)acetyl)oxazolidin-2-one in 150 cm3 of tetrahydrofuran, the mixture is stirred for 45 minutes at this temperature and then 7.72 cm3 of methyl iodide are added. The reaction mixture is then stirred for 15 hours at room temperature, then diluted with ethyl acetate, washed with 50 cm3 of water and then with 50 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa).The residue obtained is crystallized from isopropyl ether, filtered off and dried. There are obtained 4.2 g of (4S,5S)-4 methyl-5-phenyl-3- ((S) -2- (2-methoxyphenyl) propionyl) - oxazolidin-2-one in the form of a white solid.

(4S,5S)-4-Methyl-5-phenyl-3-C(2-methoxy- phenyl)acetyl)oxazolidin-2-one can be obtained in the following way: 9.38 g of 2-methoxyphenylacetic acid are added at room temperature to a suspension of 1.89 g of sodium hydride (80 % dispersion in petroleum jelly) in 200 cm3 of dry tetrahydrofuran. This suspension is cooled to -300C, 7.77 cm3 of pivaloyl chloride are added and then a solution, cooled to -780C, obtained by adding a solution of 35.27 cm3 of 1.6M butyllithium in hexane to a solution, cooled to -780C, of 10 g of (4S,5S)-4-methyl-5-phenyloxazolidin-2-one in 200 cm3 of dry tetrahydrofuran is finally added.The reaction mixture is stirred for 45 minutes at -300C and then, after returning to room temperature, 200 cm3 of a saturated aqueous ammonium chloride solution and then 500 cm3 of ethyl acetate are added; after separating by settling, the organic phase is washed twice with 100 cm3 of water and then twice with 100 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 4.8 cm, height 36 cm), eluting under a pressure of 0.6 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (85/15 and then 80/20 by volume) and collecting 50 cm3 fractions.Fractions 14 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). There are obtained 13.6 g of (4S,5S)-4-methyl-5-phenyl-3-( (2- methoxyphenyl)acetyl)oxazolidin-2-one in the form of a yellow oil.

The combinations according to the invention are particularly advantageous in the fields where Substance P, neurokinin A and NK1 and NK2 receptors are involved.

The present invention also provides pharmaceutical compositions comprising the synergistic combination consisting of at least one antagonist of NK1 receptors and of at least one antagonist of NK2 receptors in the pure state or in the form of a combination with one or more compatible and pharmaceutically acceptable adjuvants and/or diluents and/or optionally in combination with any other physiologically active, pharmaceutically compatible product. The compositions according to the invention can be used parenterally, orally, rectally or topically.

The sterile compositions for parenteral administration, which can be especially used in the form of perfusions, are preferably emulsions, suspensions or aqueous or non-aqueous solutions. Water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate, or other suitable organic solvents can be used as solvent or vehicle.

These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, for example by aseptic filtration, by incorporating sterilizing agents in the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in a sterile injectable medium.

The compositions for rectal administration are suppositories or rectal capsules which contain, beside the active product, excipients such as cocoa butter, semi-synthetic glycerides or poly(ethylene glycol) s.

Gelatin capsules, tablets, pills, powders or granules can be used as solid compositions for oral administration. In these compositions, the active product according to the invention (optionally in combination with another pharmaceutically compatible product) is mixed with one or a number of inert adjuvants or diluents, such as sucrose, lactose or starch. These compositions can also comprise substances other than the diluents, for example a lubricant such as magnesium stearate.

Solutions, suspensions, syrups, elixirs and pharmaceutically acceptable emulsions containing inert diluents such as water or liquid paraffin can be used as liquid compositions for oral administration. These compositions can also comprise substances other than the diluents, for example wetting, sweetening or flavouring products.

The compositions for topical administration can be, for example, creams, ointments or lotions.

In human therapeutics, the combinations according to the invention can be particularly useful in the treatment of pain of traumatic, post-surgical, menstrual or cranial origin, in treatments of anxiety, of psychoses, Parkinson's disease, schizophrenia or of Alzheimer's disease, in muscle-relaxing treatments, in treatments of spasmodic, painful and inflammatory manifestations of the digestive tract (ulcerative colites, irritable bowel syndrome, Crohn's disease), of the urinary tract (cystites) and of the respiratory tract (chronic bronchitis, asthma, rhinites) or in gynaecology and in treatments of migraines. The new combinations are also useful in the treatment of rheumatoid arthritis and in disorders due to disturbance of the immune system, in treatments of dermatological inflammations such as psoriasis, herpes, urticarias, eczemas, photodermatoses and in ocular or dental inflammatory disorders.

The combinations according to the invention can also find an application in treatments of cardiovascular disorders such as hypotension, or in the treatment of disorders related to poor growth regulation (dwarfism, secondary hypotrophias of chronic infantile diseases, osteoporosis, graft development).

The doses depend on the desired effect and on the duration of treatment. For an adult, they are generally between 0.25 and 1500 mg of the combination daily taken in stages.

Generally, the doctor will determine the dosage which he considers the most appropriate depending on the age, weight and all the other factors specific to the subject to be treated.

The following example illustrates a composition according to the invention.

Example Tablets containing active product are prepared, according to the usual technique, which have the following composition: - (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2- [(S)-2-(2-methoxyphenyl)propionyl)perhydroiso- indol-4-ol ............................. 12.5 mg - N-methyl-N- (4- (4-phenyl-4-acetamidopiperidinyl) -2- (3,4-dichlorophenyl)butyl]benzamide .... 12.5 mg - ................................. starch 83 mg - ................................. silica 30 mg - magnesium stearate ..................... 3 mg

Claims (9)

1. A combination of at least one compound endowed with an antagonist activity towards NK1 receptors and at least one compound endowed with an antagonist activity towards NK2 receptors.

2. A combination according to claim 1, in which the antagonist of NK1 receptors is chosen from derivatives of the perhydroisoindole class, derivatives of the 2-substituted-3-aminoquinuclidine class, derivatives of the aminoazabicycloalkane class, derivatives of the 2-substituted-3-aminopiperidine class, derivatives of the 1-azabicyclo(3.2 .2)nonan-3- amine class, derivatives of the N-alkylquinuclidinium salt class, derivatives of the pseudopeptide class, derivatives of the diacylpiperazine class, substituted aromatic derivatives, dialkylenepiperidino derivatives or substituted piperidine quaternary salts.

3. A combination according to Claim 1 in which the antagonist of NK1 receptors is (3aS,4S,7aS) 7,7-diphenyl-4-(2-methoxyphenyl) -2-( (S) -2-(2- methoxyphenyl)propionyl)perhydroisoindol-4-ol, 3-( (2- methorxyphenyl) )methylamino)-2-phenylpiperdine, or (3aR,7aR) -2-(1-imino-2-(2-methoxyphenyl)ethylj-7,7- diphenylperhydroisoindol-4-one.

4. A combination according to claim 1, 2 or 3 in which the antagonist of NK2 receptors is chosen from compounds of the arylalkylamine class, of the a-substituted polypeptide class or of the piperidine derivative class.

5. A combination according to Claim 1, 2 or 3 in which the antagonist of NK2 receptors is N-methyl N-(4- (4-phenyl-4-acetamidopiperidinyl) -2- (3,4- dichlorophenyl) -butyl)benzamide.

6. A combination according to any one of Claims 1 to 5 in the form of a pharmaceutical composition, comprising a said combination and one or more compatible and pharmaceutically acceptable adjuvants or diluents.

7. A combination according to Claim 1 substantially as hereinbefore described.

8. Use of a compound endowed with an antagonist activity towards NK1 receptors in the manufacture of a combination according to any one of claims 1 to 7.

9. Use of a compound endowed with an antagonist activity towards NK2 receptors in the manufacture of a combination according to any one of claims 1 to 7.